Interleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in the regulation of immune responses, such as stimulation of differentiated functions of B and T lymphocytes, enhancement of hematopoiesis and production of mature myeloid cells and megakaryocytes, and induction of liver acute phase proteins (for review, see refs. 1-3). It has been shown that IL-6, alone or in combination with other cytokines, also acts as a differentiation inducing factor and as a growth inhibitor of certain malignant cell types.
Experiments in vitro showed that the growth of human breast carcinoma lines MCF-7, SK-BR3, T47D and ZR-75.1 was inhibited by human recombinant IL-6 (rIL-6). In murine and human myeloid leukemia lines, human rIL-6 induced terminal differentiation and growth arrest and in fresh leukemic cells isolated from acute myeloid leukemia (AML) patients, treatment with human rIL-6 increased the proportion of cells with a differentiated phenotype. In vivo experiments using FBL-3 erythroleukemia showed that administration of high does human rIL-6 induced a strong anti-tumor CTL activity that cured the tumor-bearing mice. Experiments with several moderately immunogenic, metastatic murine sarcoma lines (MCA 105,106,203) and a colon carcinoma line MC-38 showed that systemic administration of human rIL-6 reduced substantially the number of metastatic lesions.
The Lewis lung carcinoma (3LL) clone D122 is low-immunogenic and high-metastatic in syngeneic C57BL/6 mice. These cells express low levels of H-2K.sup.b transfectants while elevating their immunogenicity (5). Experiments by the inventors have shown that administration of human rIL-6 through various protocols to mice inoculated intravenously or intra-footpad with D122 cells did not affect the malignancy of tumor cells (unpublished results). These observations can be explained either by insensitivity of D122 cells to direct or indirect (via the immune system) effects of IL-6, or by problems involved in the administration procedure in vivo such as short half-life and insufficient local levels at the tumor site of the systemically injected cytokine. It would be highly desirable to produce IL-6 constitutively in vivo and thus overcome the limitations of the systemic administration of IL-6.